title: Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: Implications in dopamine cytotoxicity and pathogenesis of Parkinson's disease.
abstract: The study has demonstrated that dopamine induces membrane depolarization and a loss of phosphorylation capacity in dose-dependent manner in isolated rat brain mitochondria during extended in vitro incubation and the phenomena are not prevented by oxyradical scavengers or metal chelators. Dopamine effects on brain mitochondria are, however, markedly prevented by reduced glutathione and N-acetyl cysteine and promoted by tyrosinase present in the incubation medium. The results imply that quinone oxidation products of dopamine are involved in mitochondrial damage under this condition. When PC12 cells are exposed to dopamine in varying concentrations (100-400μM) for up to 24h, a pronounced impairment of mitochondrial bio-energetic functions at several levels is observed along with a significant (nearly 40%) loss of cell viability with features of apoptotic nuclear changes and increased activities of caspase 3 and caspase 9 and all these effects of dopamine are remarkably prevented by N-acetyl cysteine. N-acetyl cysteine also blocks nearly completely the dopamine induced increase in reactive oxygen species production and the formation of quinoprotein adducts in mitochondrial fraction within PC12 cells and also the accumulation of quinone products in the culture medium. Clorgyline, an inhibitor of MAO-A, markedly decreases the formation of reactive oxygen species in PC12 cells upon dopamine exposure but has only mild protective actions against quinoprotein adduct formation, mitochondrial dysfunctions, cell death and caspase activation induced by dopamine. The results have indicated that quinone oxidation products and not reactive oxygen species are primarily involved in cytotoxic effects of dopamine and the mitochondrial impairment plays a central role in the latter process. The data have clear implications in the pathogenesis of Parkinson's disease.
authors.affiliation: Department of Biochemistry, Institute of Post-graduate Medical Education & Research, 244, A J C Bose Road, Kolkata, India.
authors.forename: Sirsendu
authors.initials: S
authors.lastname: Jana
authors.forename: Maitrayee
authors.initials: M
authors.lastname: Sinha
authors.forename: Dalia
authors.initials: D
authors.lastname: Chanda
authors.forename: Tapasi
authors.initials: T
authors.lastname: Roy
authors.forename: Kalpita
authors.initials: K
authors.lastname: Banerjee
authors.forename: Soumyabrata
authors.initials: S
authors.lastname: Munshi
authors.forename: Birija S
authors.initials: BS
authors.lastname: Patro
authors.forename: Sasanka
authors.initials: S
authors.lastname: Chakrabarti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects; D016716:PC12 Cells; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism; D011809:Quinones / Q000633:toxicity*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D011809:Quinones; D017382:Reactive Oxygen Species; D020169:Caspases; D004298:Dopamine